A number of kinase inhibitors have been developed as antitumor agents. For example, a group of compounds having inhibitory activity against receptor tyrosine kinases, such as vascular endothelial growth factor receptor (VEGFR), are known to inhibit angiogenesis and are regarded as a new class of antitumor agents. Lenvatinib mesylate (also known as E7080) is an oral tyrosine kinase inhibitor targeting VEGFR1-3, fibroblast growth factor receptor (FGFR) 1-4, rearranged during transfection receptor (RET), KIT, and platelet-derived growth factor receptor (PDGFR). In phase I clinical studies of lenvatinib mesylate, response to treatment was observed in various tumor types, e.g., endometrial cancers.
Unfortunately, most anti-tumor treatments are associated with undesirable side effects, such as profound nausea, vomiting, or severe fatigue. Also, while anti-tumor treatments have been successful, they do not produce significant clinical responses in all patients who receive them, resulting in undesirable side effects, delays, and costs associated with ineffective treatment. Therefore, biomarkers that can be used to predict the response of a subject to an antitumor agent prior to administration thereof are greatly needed.
WO 2012/157672 discloses that, in a sub-group of melanoma patients who either have wild type B-raf and PTEN or mutated B-raf and PTEN, high levels of Ang2, IL6, CXCR4, COL4A3, MEIS1, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, or VEGFR1 and low levels of SHC1, NRP2, ARHGAP22, SCG2, or PML are predictive of responsiveness to lenvatinib compounds.
WO 2012/166899 discloses that, in subjects having thyroid or kidney cancer, low levels of Ang2, VEGFA, IFNG, or soluble KDR or high levels of IL-6, IL-13, PDGFAB, CSF3, CCL3, CCL4, FLT4, or FGF2 are predictive of responsiveness to lenvatinib compounds. However, WO 2012/166899 does not disclose or suggest that Ang2 can be used as predictive of responsiveness to lenvatinib compounds in endometrial cancer patients.
Llovet et al. Clin Cancer Res., 18(8):2290-2300 (2012), reports that in patients with advanced hepatocellular carcinoma, while the angiogenesis biomarkers Ang2 and VEGF were predictors of survival, these biomarkers were not predictive of responsiveness to the angiogenesis inhibitor, sorafenib.
Thus, an angiogenesis biomarker like Ang2 is not expected to serve as a biomarker for responsiveness to angiogenesis inhibitors in all cancers.